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Query: UNIPROT:P06889 (Mol)
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A late onset neurological syndrome in carriers of premutation in FMR1 gene was recently described. The condition was named fragile-X-associated tremor/ataxia syndrome (FXTAS) and includes intentional tremor, cerebellar ataxia, parkinsonism, and cognitive deficit. We ascertained the contribution of FMR1 premutation to the phenotypes ataxia, tremor and/or parkinsonism. Sixty-six men over 45 years old presenting these symptoms, isolated or combined, were tested. Also, 74 normal men, randomly chosen in the population, formed the control group. In the patient group, no premutation carrier was found, which is in agreement with other observed frequencies reported elsewhere (0-5% variation). No significant differences were found when comparing gray zone allele frequencies among target and control groups. The FXTAS contribution in patients with phenotypic manifestations of FXTAS was 15/748 (2%). The presence of gray zone alleles is not correlated with FXTAS occurrence.
Genet Mol Res 2008 Jan 29
PMID:Frequency of FMR1 premutation in individuals with ataxia and/or tremor and/or parkinsonism. 1827 22

The molecular diagnosis of fragile X syndrome relies on the detection of the pathogenic CGG repeat expansion in the FMR1 gene. Deletions and point mutations have occasionally been reported. Rare polymorphisms might mimic a deletion by Southern blot analysis, leading to false-positive results. We describe a novel rare nucleotide substitution within the CGG repeat. The proband was a woman with a positive family history of mental retardation. Southern blot analysis showed an additional band consistent with a deletion in the region detected by the StB12.3 probe. Sequencing of this region revealed a G>C transversion that interrupts the CGG repeat and introduces an EagI site. The same variant was observed in both the healthy son and father of the proband, supporting the hypothesis that the nucleotide substitution is a silent polymorphism, the frequency of which we estimated to be less than 1% in the general population. These findings argue for a pathogenic role of nucleotide variants within the CGG repeat and suggest possible consequences of unexpected findings in the molecular diagnostics of fragile X syndrome. Thus, although the sequence context of a single nucleotide substitution may not predict possible effects on mRNA or protein function, a specific change in the higher order structures of DNA or mRNA may be functionally relevant in the pathological phenotype.
J Mol Diagn 2008 May
PMID:A single nucleotide variant in the FMR1 CGG repeat results in a "Pseudodeletion" and is not associated with the fragile X syndrome phenotype. 1840 14

Fragile X syndrome, the most common form of inherited mental retardation is caused by mutations in the FMR1 gene. FMR1 encodes an RNA-binding protein thought to control the transport and translation of target mRNAs. While the function of FMRP in translational control has been clearly demonstrated, its role in mRNA transport and localization in neurons remains elusive. Using a genetically encoded mRNA imaging system in Drosophila we provide the first demonstration that FMRP controls mRNA transport. Live imaging of FMRP associated mRNAs show that mRNA granules are less motile and exhibit decreased directional movement in dFmr1 mutant neurons. Furthermore, Fluorescence Recovery After Photobleaching experiments show that the mobile fraction of mRNA molecules within neurites is dependent on FMRP dosage. These data support a model whereby FMRP regulates transport efficacy, by regulating the association between mRNA cargo and microtubules and suggest a new mechanism for the disease.
Mol Cell Neurosci 2008 Oct
PMID:Fragile X protein controls the efficacy of mRNA transport in Drosophila neurons. 1865 36

The fragile X mental retardation protein FMRP is an RNA binding protein that associates with a large collection of mRNAs. Since FMRP was previously shown to be a nucleocytoplasmic shuttling protein, we examined the hypothesis that FMRP binds its cargo mRNAs in the nucleus. The enhanced green fluorescent protein-tagged FMRP construct (EGFP-FMRP) expressed in Cos-7 cells was efficiently exported from the nucleus in the absence of its nuclear export sequence and in the presence of a strong nuclear localization sequence (the simian virus 40 [SV40] NLS), suggesting an efficient mechanism for nuclear export. We hypothesized that nuclear FMRP exits the nucleus through its bound mRNAs. Using silencing RNAs to the bulk mRNA exporter Tap/NXF1, we observed a significantly increased number of cells containing EGFP-FMRP in the nucleus, which was further augmented by removal of FMRP's nuclear export sequence. Nuclear-retained SV40-FMRP could be released upon treatment with RNase. Further, Tap/NXF1 coimmunoprecipitated with EGFP-FMRP in an RNA-dependent manner and contained the FMR1 mRNA. To determine whether FMRP binds pre-mRNAs cotranscriptionally, we expressed hemagglutinin-SV40 FMRP in amphibian oocytes and found it, as well as endogenous Xenopus FMRP, on the active transcription units of lampbrush chromosomes. Collectively, our data provide the first lines of evidence that FMRP binds mRNA in the nucleus.
Mol Cell Biol 2009 Jan
PMID:Fragile X mental retardation protein FMRP binds mRNAs in the nucleus. 1893 62

Fragile X syndrome, the most prevalent inherited cause of mental retardation, is related to hyperexpansion of a polymorphic CGG repeat of the FMR1 gene. Expansion of 55-200 repeats are called premutations and characterize carriers who usually have no mental impairment. The disease causing full mutations exceed 200 CGG repeats, are hypermethylated and lead to transcriptional silencing of the gene and absence of the Fragile X mental retardation protein (FMRP). Diagnostic approaches involve molecular and immunocytochemical techniques. Southern blot, which allows mutations to be detected and methylation status to be determined in a single test, remains the procedure of choice for most laboratories. Modifications of PCR methods, including methylation specific PCR, are also proposed but their implementation is still in question because of inherent difficulties to amplify CGG repeats, distinguish between mosaic patterns and interpret results in female individuals. The FMRP antibody test is also suitable for large population screening and elucidation of Fragile X syndrome cases with no CGG expansion, but it is not widely applied. In search for novel diagnostic approaches, use of PCR as a first prescreening test followed by Southern blot is considered the most reliable procedure.
Expert Rev Mol Diagn 2009 Jan
PMID:Molecular diagnosis of Fragile X syndrome. 1909 46

Mice lacking the gene encoding fragile X mental retardation protein (FMR1) are susceptible to audiogenic seizures, and antagonists of the group I metabotropic glutamate receptors (mGluRs) have been shown to block seizures in FMR1 knockout mice. We investigated whether the G-protein-inhibitory activity of the regulator of G-protein signaling protein, RGS4, could also alter the susceptibility to audiogenic seizures in FMR1 mice. We were surprised to find that male FMR1/RGS4 double-knockout mice showed reduced susceptibility to audiogenic seizures compared with age-matched FMR1 mice. These data raised the intriguing possibility that loss of RGS4 increased signaling through another G-protein pathway that reduces seizure susceptibility in FMR1 mice. Indeed, administration of the GABA(B) receptor agonist baclofen to FMR1 mice inhibited seizures, whereas the GABA(B) receptor antagonist (3-aminopropyl)(cyclohexylmethyl)phosphinic acid (CGP 46381) increased seizure incidence in double-knockout mice but not in wild-type mice. Finally, audiogenic seizures could be induced in wild-type mice by coadministering CGP 46381 and the mGluR5-positive allosteric modulator 3-cyano-N-(1,2 diphenyl-1H-pyrazol-5-yl) benzamide. These data show for the first time that GABA(B) receptor-mediated signaling antagonizes the seizure-promoting effects of the mGluRs in FMR1 knockout mice and point to the potential therapeutic benefit of GABA(B) agonists for the treatment of fragile X syndrome.
Mol Pharmacol 2009 Jul
PMID:Increased GABA(B) receptor-mediated signaling reduces the susceptibility of fragile X knockout mice to audiogenic seizures. 1935 45

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a progressive neurodegenerative disorder that has been diagnosed in a substantial fraction of older male fragile X premutation carriers. Patients affected by FXTAS have elevated levels of ribo-rCGG repeat containing FMR1 mRNA with normal to slightly reduced levels of FMRP in blood leukocytes. Coupled with the absence of FXTAS in fragile X syndrome patients, this suggests premutation-sized elongated rCGG repeats in the FMR1 transcript rather than alterations in the levels of FMRP are responsible for the FXTAS pathology. Mice expressing rCGG in the context of Fmr1 or the enhanced green fluorescent protein specifically in Purkinje neurons were generated to segregate the effects of rCGG from alterations in Fmr1 and to provide evidence that rCGG is necessary and sufficient to cause pathology similar to human FXTAS. The models exhibit the presence of intranuclear inclusions in Purkinje neurons, Purkinje neuron cell death and behavioral deficits. These results demonstrate that rCGG expressed in Purkinje neurons outside the context of Fmr1 mRNA can result in neuronal pathology in a mammalian system and demonstrate that expanded CGG repeats in RNA are the likely cause of the neurodegeneration in FXTAS.
Hum Mol Genet 2009 Jul 01
PMID:Ectopic expression of CGG containing mRNA is neurotoxic in mammals. 1937 84

Fragile X syndrome, which is caused by expanded CGG repeats of the FMR1 gene, is associated with a broad spectrum of clinical involvement and is the most common inherited form of intellectual disability. Early diagnosis and intervention are likely to lead to improved outcome for children with fragile X syndrome, but such strategies require better estimates of the frequencies of expanded alleles of the FMR1 gene. In this study, we report the results of a newborn screening study of 5267 male blood spots collected from the Northwest region of Spain as part of the national newborn screening program. The blood spots were screened using a rapid polymerase chain reaction-based method that is capable of identifying the presence of all expanded alleles for both males and females. The screened samples included 199 gray zone alleles, 21 premutation alleles, and two full mutation alleles (1 in 2633). The frequency of premutation alleles was three times higher (1 in 251) than the quoted value of 1 in 813 from a Canadian population and is fully consistent with the results of large-scale Israeli screening studies. Our results demonstrate that newborn screening for the presence of expanded FMR1 alleles is an effective means for defining the distribution of expanded FMR1 alleles in newborn populations; as such, this method is suitable for large-scale newborn screening.
J Mol Diagn 2009 Jul
PMID:Screening for expanded alleles of the FMR1 gene in blood spots from newborn males in a Spanish population. 1946 Sep 41

Fragile X Syndrome is caused by the expansion of an unstable CGG-repeat tract in the 5'-UTR of the FMR1 gene, which generally results in transcriptional silencing and consequent absence of the FMR1 protein. To date, the smallest premutation allele reported to expand to a full mutation allele in a single generation is 59 CGG repeats. Here, we report a single-generation expansion to a full mutation allele (male with approximately 538 CCG repeats) from a mother who is a carrier of a premutation allele of 56 CGG repeats. Furthermore, the maternal grandfather was a carrier of a gray (or intermediate)-zone allele (45 to 54 repeats) of 52 CGG repeats. Thus, in this family, a gray-zone allele expanded to the full mutation range in two generations. Interestingly, the two AGG interruptions present in the grandfather's allele were absent in the mother's premutation allele. These observations underscore the need to consider carriers of alleles of greater than 55 CGG repeats as being at risk for transmission of a full mutation allele in a single generation, and those with even smaller alleles in the gray zone as being at risk of having grandchildren with full mutation alleles.
J Mol Diagn 2009 Jul
PMID:Expansion of an FMR1 grey-zone allele to a full mutation in two generations. 1952 39

Most common inherited form of intellectual disability, fragile X syndrome is associated to an expansion of greater than 200 CGG repeats in the 5' untranslated region of the FMR1 gene on the X chromosome which causes transcriptional silencing and deficiency of the encoded protein FMRP. Molecular diagnosis is performed through a combination of PCR to identify fewer than 100-150 repeats and of Southern blot analysis to identify longer alleles and the methylation status of the FMR1 promoter. We present a family with one patient with mild mental retardation who showed an atypical profile at Southern analysis due to the -413C > G transversion located in the FMR1 promoter which had been described as possibly associated with mental retardation. We demonstrated this variant in other four family members along three generations, including the maternal grandfather who did not manifest any pathological feature. Though the -413C > G substitution was not found in a large control series, these findings allowed to exclude its role in determining the disease phenotype.
Mol Cell Probes 2010 Apr
PMID:The -413C > G substitution in the promoter of the FMR1 gene is not associated with the fragile X syndrome phenotype. 1983 46


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